Clot formation resulting in the blockage of a major coronary artery can lead to myocardial infarction, one of the most common causes of death in industrialized societies. Enzymatic recanalization of an occluded coronary artery with a drug such as streptokinase or tissue plasminogen activator (tpa) has been shown to reduce mortality significantly in patients suffering from acute myocardial infarction (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) Lancet 2:871-874, 1987; Wilcox RG, Lancet 2:525-530, 1988; ISIS-2 Collaborative Study Group, Lancet 2:349-360, 1988). However, limitations of thrombolytic therapy include a very high rate of reocclusion (Gold et al., Circulation 73:347-352, 1986) and the relative resistance of arterial clots to lysis (Jang et al., Circulation 79:920-928, 1989). Acute thrombotic reocclusion is also a frequent and major setback after otherwise successful percutaneous transluminal coronary angioplasty (PTCA) (Detre et al., Circulation 80:421-428, 1989), and constitutes a formidable problem after the placement of intracoronary stents (Roubin et al., Circulation 85:916-927, 1992). Adjunctive therapy with currently available antiplatelet (ISIS-2 supra) and anticoagulant (Hsia et al., N Engl J Med 323:1433-1437, 1990) agents has shown some benefit in overcoming these difficulties and also in reducing restenosis (Hanke et al., Circulation 85:1548-1556, 1992).
Thrombin is an enzyme in blood that plays a central role in blood clot development by catalyzing the formation of fibrin from fibrinogen and, perhaps more importantly, as the most potent activator of platelets. The anti-coagulant, heparin, has been shown to be of only limited efficacy in antagonizing the action of thrombin in experimental studies. A number of direct inhibitors of thrombin have been shown to be effective in preventing platelet-dependent arterial thrombosis and rethrombosis after thrombolytic reperfusion in experimental animals (Haskel, Circulation 83:1048-1056, 1991; Jang et al., Circ. Res. 67:1552-1561, 1990; Heras et al., Circulation 82:1476-1484, 1990; Kelly et al., Blood 77:1006-1012, 1991; Sitko et al., Circulation 85:805-815, 1992). One of these thrombin antagonists is hirudin, an anti-coagulant derived from the leech, Hirudo medicinalis (Dodt et al., FEBS 165:180-184, 1984).
Plasminogen activators, such as streptokinase and urokinase, catalyze the conversion of plasminogen to its active fibrinolytic form, plasmin. These reagents activate circulating as well as fibrin-bound plasminogen and thus not only affect the lysis of fibrin in the thrombus, but also promote fibrinolysis elsewhere in the body. Tissue-type plasminogen activator has somewhat improved the specificity problem, but therapeutic administration of both fibrinolytic agents and thrombin inhibitors is still a problem because of their lack of selectivity and potential to cause generalized hemorrhaging.